Involvement of NADPH Oxidase 1 in Liver Kinase B1-Mediated Effects on Tumor Angiogenesis and Growth

Abstract

The liver kinase B1 (LKB1) gene is a tumor suppressor with an established role in the control of cell metabolism and oxidative stress. However, whether dis-regulated oxidative stress promotes growth of LKB1-deficient tumors remains substantially unknown. Through in vitro studies, we observed that loss of LKB1 perturbed expression of several genes involved in reactive oxygen species (ROS) homeostasis. In particular, this analysis evidenced strongly up-modulated NADPH oxidase 1 (NOX1) transcript levels in tumor cells lacking LKB1. NOX1 accounted in part for enhanced cytotoxic effects of H2O2-induced oxidative stress in A549 LKB1-deficient tumor cells. Notably, genetic and pharmacologic inhibition of NOX1 activity reduced angiogenesis and growth of A549 tumors in mice. These results suggest that NOX1 inhibitors could counteract ROS production and the angiogenic switch in LKB1-deficient tumors.

LKB1 and Tumor Metabolism: The Interplay of Immune and Angiogenic Microenvironment in Lung Cancer

“…Altogether, preclinical studies support the hypothesis that LKB1 triggers complex changes in the tumor microenvironment involving different targets that impact directly or indirectly on VEGF signaling and possibly other additional angiogenic pathways [42] (Figure 1).…”

“…In addition, we recently demonstrated that LKB1 acts as a suppressor of NADPH oxidase 1 ( NOX1 ) expression at transcript levels [42]. NADPH oxidases catalyze the transfer of one electron from NADPH to oxygen, generating superoxide or H 2 O 2 , thus resulting in increased oxidative stress [43].…”

“…Moreover, NOX1 has been associated in the promotion of angiogenic switch by a mechanism involving ROS generation and increased expression of VEGF [45]. Interestingly, genetic and pharmacological inactivation of NOX1 activity prevents the angiogenic switch and the growth of experimental tumors derived from NSCLC LKB1-deficient cancer cells [42].…”

“…As described above, several clinical and pre-clinical evidences support a role of LKB1 as modulator of tumor microenvironment, through direct influence on angiogenesis and on the immune landscape. Specifically, LKB1 loss directly or indirectly impacts on VEGF signaling and possibly on other additional angiogenesis pathways, leading to promotion of angiogenesis [42] and, in parallel, a lack of LKB1 activity within tumor cells is related to the creation of an immunosuppressive microenvironment [80] (Figure 1).…”

STK11 (LKB1) missense somatic mutant isoforms promote tumor growth, motility and inflammation

“…LKB1-AMPK-stimulated pathways also include increased turnover of macromolecules by autophagy, allowing the turnover of old and damaged molecules, or the replenishment of nutrient stores under starvation 20 . Additionally, several investigations have suggested the role of LKB1 in regulation of physiological 21 and pathological angiogenesis 22 through the regulation of VEGF, MMP-2, MMP-9, bFGF, and NOX1 expression, and its participation in neurophilin-1 degradation 23 – 25 . Studies of LKB1 loss of function have also revealed its role in cell polarity and motility through the regulation of PAK1 15 and the modulation of the phosphorylation status of FAK and CDC42 activation 26 .…”